1Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.
2Microbiology Research Center (MRC), Pasteur Institute of Iran, No. 358, 12th Farvardin Ave, Jomhoori St, Tehran, 1316943551 Iran.
Antimicrob Resist Infect Control. 2019 May 2;8:70. doi: 10.1186/s13756-019-0516-4. eCollection 2019.
In order to shorten the course of treatment and its effectiveness, it is essential to gain an in-depth insight into the drug resistance mechanisms of ().
In this study, we evaluated the contribution of 26 drug efflux pumps plus target gene mutations to the drug resistance levels in multi-drug resistant (MDR)/pre-extensively drug-resistant (pre-XDR)/extensively drug-resistant (XDR) and mono-drug resistant clinical isolates of . The panels of 25 clinical strains were characterized for drug resistance-associated mutations with whole-genome sequencing and antibiotic profiles in the presence and absence of efflux inhibitor verapamil (VP).
Different MICs were observed for the same target gene mutations. Out of the 16 MDR/pre-XDR/XDR isolates, 6 (37.5%) and 3 (18.8%) isolates demonstrated a significant decrease in rifampicin (RIF) MIC and isoniazid (INH) MIC due to the VP exposure (64 μg/mL), respectively. Susceptibility to RIF was fully restored in two isolates after VP exposure. Moreover, the efflux pump genes of , and were overexpressed in the presence of anti-TB drugs, showing the contribution of these efflux pumps to the overall resistance phenotype.
Our results clearly showed that efflux systems, besides spontaneous mutations, play a role in the development of INH/RIF resistance. In addition, although VP was effective in reducing the expression of some efflux pumps, it was not very successful at the phenotypic level.
为了缩短治疗疗程和提高疗效，深入了解（）的耐药机制至关重要。
本研究通过评估 26 种外排泵加上靶基因突变对多药耐药（MDR）/预广泛耐药（pre-XDR）/广泛耐药（XDR）和单药耐药临床分离株的药物耐药水平的贡献，来研究这一问题。我们对 25 株临床分离株的耐药相关基因突变进行了全基因组测序，并在存在和不存在外排泵抑制剂维拉帕米（VP）的情况下进行了抗生素谱分析。
对于相同的靶基因突变，观察到不同的 MIC 值。在 16 株 MDR/pre-XDR/XDR 分离株中，由于 VP（64μg/mL）暴露，6 株（37.5%）和 3 株（18.8%）分离株利福平（RIF）MIC 和异烟肼（INH）MIC 显著降低。在 VP 暴露后，两株分离株对 RIF 的敏感性完全恢复。此外，在抗结核药物存在的情况下， 、 和 的外排泵基因过度表达，表明这些外排泵对整体耐药表型有贡献。
我们的研究结果清楚地表明，外排系统除了自发突变外，还在 INH/RIF 耐药的发展中起作用。此外，尽管 VP 有效降低了一些外排泵的表达，但在表型水平上并不十分成功。
